This randomised, open-label, phase III study will be performed in patients with R/M head and neck squamous cell carcinoma (HNSCC) who have progressed after platinum-based therapy. The objectives of the trial are to compare the efficacy and safety of afatinib versus methotrexate

Progression-free Survival (PFS) Based on Central Independent Review [ Time Frame: From randomization until disease progression, death or data cut-off (07May2014); Up to 28 months ] [ Designated as safety issue: No ]

PFS was defined as the time from the date of randomisation to disease progression or death, whichever occurred first. The primary analysis of PFS considered PFS events as assessed by central independent review, including all data collected until the cut-off date (7 May 2014).

The date of disease progression was recorded based on RECIST version 1.1. Unequivocal progression of disease was determined if at least one of the following criteria applied:

At least 20% increase in the SoD of target lesions taking as reference the smallest SoD recorded since the treatment started, together with an absolute increase in the SoD of at least 5 mm

Appearance of one or more new lesions

Unequivocal progression of existing non-target lesions

Secondary Outcome Measures:

Overall Survival (OS) [ Time Frame: From randomization until death or data cut-off (30Jun2014); Up to 29 months ] [ Designated as safety issue: No ]

Overall survival (OS) was a key secondary endpoint of this trial. OS was defined as the time from randomisation to death (irrespective of the cause of death). Patients for whom there was no evidence of death at the cut-off date (30 Jun 2014) were to be censored on the date that they were last known to be alive.

Objective Response (OR) [ Time Frame: Tumour imaging was to be performed every 6 weeks during the first 24 weeks of treatment, and hereafter every 8 weeks (Up to 28 months) ] [ Designated as safety issue: No ]

OR is defined as the best overall response of complete response (CR) and partial response (PR) according to RECIST version 1.1, CR for target lesions (TL): Disappearance of all target lesions. CR for non-target lesions (NTL): Disappearance of all non-target lesions. All lymph nodes must be non-pathological in size (<10mm short axis).

PR for TL: At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters.

Other factors which add to the overall response of an imaging timepoint as PR are as below:-

CR in TL, but non-CR/Non-PD in NTL leads to PR

CR in TL, but not evaluated NTL leads to PR

PR in TL, but non-PD NTL or not all evaluated NTL leads to PR;

All the above scenarios should also satisfy 'No occurrence of new lesions'.

Disease Control (DC) [ Time Frame: Tumour imaging was to be performed every 6 weeks during the first 24 weeks of treatment, and hereafter every 8 weeks (Up to 28 months) ] [ Designated as safety issue: No ]

DC is defined as the best overall response of CR, PR, stable disease (SD) and non-CR/non-PD.

CR for target lesions (TL): Disappearance of all target lesions. CR for non-target lesions (NTL): Disappearance of all non-target lesions . All lymph nodes must be non-pathological in size (<10mm short axis).

PR for TL: At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters.

Other factors which add to the overall response of an imaging timepoint as PR are as below:-

CR in TL, but non-CR/Non-PD in NTL leads to PR

CR in TL, but not evaluated NTL leads to PR

PR in TL, but non-PD NTL or not all evaluated NTL leads to PR;

SD for TL: change in the sum of diameters does not satisfy PR or PD.

SD in TL, non-PD in NTL lead to overall response of SD, provided there is no appearance of new lesions.

Tumour Shrinkage [ Time Frame: Tumour imaging was to be performed every 6 weeks during the first 24 weeks of treatment, and hereafter every 8 weeks (Up to 28 months) ] [ Designated as safety issue: No ]

Tumour shrinkage, defined as the maximum decrease from baseline in the sum of diameters of the target lesions, as measured by central imaging. The longest diameter of target lesions was recorded, except for lymph nodes, which were measured by their short axis.

Negative values indicate a reduction in the sum of target lesion diameters and positive values an increase.

Health Related Quality of Life (HRQOL)- Change in Pain Scores Over Time [ Time Frame: From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. ] [ Designated as safety issue: No ]

The HRQOL analyses focused on pain, swallowing, and global health status measured by the European Organisation for Research and Treatment of Cancer [EORTC] quality of life questionnaires Core 30 [QLQ-C30], and head and neck cancer specific supplementary module EORTC QLQ-H&N35:

The scores of these scales were averaged from the scores of the component items, transformed and analyzed on 0 - 100 scale. For pain and swallowing scales, higher scores represent worse outcome; for the global health/QoL scale, higher scores represent better outcome.

Changes in scores over time were assessed using longitudinal models.

The analyses of HRQOL are presented for the 07 May 2014 cut-off date.

Health Related Quality of Life (HRQOL)- Change in Swallowing Scores Over Time [ Time Frame: From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. ] [ Designated as safety issue: No ]

The HRQOL analyses focused on pain, swallowing, and global health status measured by the European Organisation for Research and Treatment of Cancer [EORTC] quality of life questionnaires Core 30 [QLQ-C30], and head and neck cancer specific supplementary module EORTC QLQ-H&N35:

The scores of these scales were averaged from the scores of the component items, transformed and analyzed on 0 - 100 scale. For pain and swallowing scales, higher scores represent worse outcome; for the global health/QoL scale, higher scores represent better outcome.

Changes in scores over time were assessed using longitudinal models.

The analyses of HRQOL are presented for the 07 May 2014 cut-off date.

Health Related Quality of Life (HRQOL)- Change in Global Health Scores Over Time [ Time Frame: From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. ] [ Designated as safety issue: No ]

The HRQOL analyses focused on pain, swallowing, and global health status measured by the European Organisation for Research and Treatment of Cancer [EORTC] quality of life questionnaires Core 30 [QLQ-C30], and head and neck cancer specific supplementary module EORTC QLQ-H&N35:

The scores of these scales were averaged from the scores of the component items, transformed and analyzed on 0 - 100 scale. For pain and swallowing scales, higher scores represent worse outcome; for the global health/QoL scale, higher scores represent better outcome.

Changes in scores over time were assessed using longitudinal models.

The analyses of HRQOL are presented for the 07 May 2014 cut-off date.

Status Change in Pain Scale [ Time Frame: From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. ] [ Designated as safety issue: No ]

Distribution of patients with improved, stable or worsened HRQOL: Improvement was defined as a score improved by at least 10 points from baseline (on the 0-100 point scale) at any time during the trial. If a patient had not improved, worsening was defined as a 10-point worsening at any time during the trial. Otherwise, a patient was considered as stable.

Status Change in Swallowing Scale [ Time Frame: From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. ] [ Designated as safety issue: No ]

Distribution of patients with improved, stable or worsened HRQOL: Improvement was defined as a score improved by at least 10 points from baseline (on the 0-100 point scale) at any time during the trial. If a patient had not improved, worsening was defined as a 10-point worsening at any time during the trial. Otherwise, a patient was considered as stable.

Status Change in Global Health Status Scale [ Time Frame: From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. ] [ Designated as safety issue: No ]

Distribution of patients with improved, stable or worsened HRQOL: Improvement was defined as a score improved by at least 10 points from baseline (on the 0-100 point scale) at any time during the trial. If a patient had not improved, worsening was defined as a 10-point worsening at any time during the trial. Otherwise, a patient was considered as stable.

Time to Deterioration in Pain [ Time Frame: From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. ] [ Designated as safety issue: No ]

The time to deterioration was defined as the time from randomisation to a score increased (i.e. worsened) by at least 10 points from baseline (0-100 point scale). If score is missing, and patient died within 28 days after scheduled time for completion, the patient was considered deteriorated. In this case, time to deterioration is time to death.

Time to Deterioration in Swallowing [ Time Frame: From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. ] [ Designated as safety issue: No ]

The time to deterioration was defined as the time from randomisation to a score increased (i.e. worsened) by at least 10 points from baseline (0-100 point scale). If score is missing, and patient died within 28 days after scheduled time for completion, the patient was considered deteriorated. In this case, time to deterioration is time to death.

Time to Deterioration in Global Health Status [ Time Frame: From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months. ] [ Designated as safety issue: No ]

The time to deterioration was defined as the time from randomisation to a score decreased (i.e. worsened) by at least 10 points from baseline (0-100 point scale). If score is missing, and patient died within 28 days after scheduled time for completion, the patient was considered deteriorated. In this case, time to deterioration is time to death.

Histologically or cytologically confirmed R/M HNSCC of the oral cavity, oropharynx, hypopharynx or larynx, not amenable for salvage surgery or radiotherapy

Documented progressive disease based on investigator assessment according to Response Evaluation Criteria in Solid Tumours (RECIST) following receipt of at least two cycles of cisplatin or carboplatin administered for R/M disease

Measurable disease according to RECIST

Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

Exclusion criteria:

Progressive disease within three months of completion of curatively intended treatment for locoregionally advanced or metastatic HNSCC

Any other than one previous platinum based systemic regimen given for R/M disease

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01345682